1-Hydroxybenzotriazole → 2-Bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester

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Reaction Conditions

Reaction Steps

Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2; 5.00 g, 19.3 mmol), HBTU (7.31 g, 19.3 mmol), 3-hydroxybenzylamine HCl salt (Example 7; 3.37 g, 21.2 mmol), and HOBT (2.6 g, 19.2 mmol) in N,N-dimethylformamide (50 mL). The solution was allowed to stir at ˜0° C. for 1 h, then at room temperature for 4 h, and it was then concentrated to remove most of the N,N-dimethylformamide. The residue was partitioned between ethyl acetate and 1 M HCl (200 mL each). The ethyl acetate layer was washed with 1 M HCl (2×100 mL) and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate layers were washed with saturated sodium hydrogen carbonate solution (2×100 mL), and brine, then dried (MgSO4), filtered, evaporated and recrystallized from hot ethyl acetate (˜60 mL) and hexanes (15 mL) to give 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (5.15 g, 73%) as white crystals.

Provenance & Evidence